Mortality in cancer is most often due to the development of distant metastases for which almost no effective systemic treatments exist. The study of genes relevant for the regulation of metastasis in vivo is therefore of great importance. The functions of p63, a p53 family member, are beginning to be understood in contexts in which p53 function has been well established, including apoptosis and tumor suppression (Su et al., Nature 2010) as well as in other roles such as metastasis (Su et al., Nature 2010), skin development, and stem cell maintenance (Su et al., Cell Stem Cell 2009). The complexity of p63 function is due in part to the existence of multiple isoforms that previously could not be studied independently. Full length TA isoforms of p63 contain a transactivation domain, structurally and functionally resembling p53, whereas the ?N isoforms of p63, while also possessing transactivation activity, antagonize the activities of p53 and the TA isoforms of p63 and p73, the other p53 family member. Interestingly, mutant p53, present in a wide variety of human cancers, has been shown to interact with p63 isoforms and inactivate their function. By generating and studying mice with isoform-specific null alleles of p63, the TAp63-/- and [delta]Np63-/- mice, we have shown that these genes have distinct roles in suppression of tumorigenesis and metastasis. TAp63-/- mice are highly susceptible to spontaneous metastatic tumors, and TAp63 potently suppresses tumor metastasis by direct coordinate transcriptional regulation of Dicer and several miRNAs (Su et al., Nature 2010). In addition, we have extended these findings to multiple human tumor types including squamous cell carcinoma, lung adenocarcinoma, and breast adenocarcinoma, indicating this function of TAp63 is widely important. We have also shown that ?Np63 can suppress invasion and transcriptionally regulates DGCR8, another critically important enzyme necessary for miRNA processing. We hypothesize that TAp63 and [delta]Np63 regulate distinct miRNAs in different cellular compartments to suppress tumorigenesis and metastasis and to engage the DNA damage response. We will address our hypothesis by proposing the following specific aims: Specific Aim 1: To understand the mechanistic regulation of miRNA and LincRNA targets by p63 isoforms in the cell of origin of carcinomas (epidermal cells). Specific Aim 2: To understand the mechanistic regulation of miRNAs and LincRNAs by p63 isoforms in stem cells of skin cancer and metastasis. Specific Aim 3: To understand the roles of miRNAs and LincRNAs regulated by p63 isoforms in the DNA damage response and p53 compensation.